Synthetic Lethality

Synthetic lethality is emerging as an important therapeutic paradigm in the treatment of cancer. It was first defined by Calvin Bridges in 1922 based on the observation that certain combinations of gene mutations resulted in lethality despite the fact the single mutations in either gene were viable.

Mutated, amplified, and deleted genes in cancer have been catalogued, and a subset of historically undruggable targets can potentially be pursued indirectly, based on the concept of synthetic lethality. For example, cancer cells with loss of function mutations in a first gene “A” may have susceptibility to pharmacological inhibition of its synthetic lethal partner, the protein product of gene “B”. For example, cancer cells often contain genetic changes that lead to alterations in pathways such as DNA repair and metabolism. These changes endow the cancer cells with certain properties such as the ability to replicate by bypassing normal control mechanisms. However, removing these important regulators of cell function may also make these cancer cells more dependent on backup pathways that can then be targeted to achieve a therapeutic effect.

IDEAYA is prosecuting a novel set of drug targets selected through consideration of the robustness and conservation of synthetic lethality interactions across different organisms and in human tumor cells, disease relevance of drug target and prevalent loss-of-function mutation in a synthetic lethality partner gene, and ability to drug the target with a small-molecule therapeutic.